Impact of Cancer, Inflammation, and No Standard Risk Factors in Patients With Myocardial Infarction

Background The lack of standard modifiable cardiovascular risk factors (SMuRFs), including hypertension, diabetes, dyslipidemia, and smoking, is reportedly associated with poor outcomes in acute myocardial infarction (AMI). Among patients with no SMuRFs, cancer and chronic systemic inflammatory diseases (CSIDs) may be major etiologies of AMI. Objectives The purpose of this study was to evaluate clinical characteristics and outcomes of patients with cancer, CSIDs, and no SMuRFs in AMI. Methods This multicenter registry included 2,480 patients with AMI undergoing percutaneous coronary intervention. Patients were divided into 4 groups: active cancer, CSIDs, no SMuRFs, and those remaining. The coprimary endpoint was major adverse cardiovascular events (MACE) and major bleeding events, during hospitalization and after discharge. Results Of 2,480 patients, 104 (4.2%), 94 (3.8%), and 120 (4.8%) were grouped as cancer, CSIDs, and no SMuRFs, respectively. During the hospitalization, MACE rates were highest in the no SMuRFs group, followed by the cancer, CSIDs, and SMuRFs groups (22.5% vs 15.4% vs 12.8% vs 10.2%; P < 0.001), whereas bleeding risks were highest in the cancer group, followed by the no SMuRFs, CSIDs, and SMuRFs groups (15.4% vs 10.8% vs 7.5% vs 4.9%; P < 0.001). After discharge, the rates of MACE (33.3% vs 22.7% vs 11.3% vs 9.2%; P < 0.001) and bleeding events (8.6% vs 6.7% vs 3.8% vs 2.9%; P = 0.01) were higher in the cancer group than in the CSIDs, no SMuRFs, and SMuRFs groups. Conclusions Patients with active cancer, CSIDs, and no SMuRFs differently had worse outcomes after AMI in ischemic and bleeding endpoints during hospitalization and/or after discharge, compared with those with SMuRFs.

setting of acute MI. [5][6][7][8] Patients with acute MI and no SMuRFs should have nonstandard cardiovascular risk factors such as disorders in sleep, nutrition, physical activity, mental and oral health, coagulation system, and genetics, among which active cancer and inflammatory diseases may be major etiologies of MI. 3 Our previous study showed that approximately one-third of patients with acute MI and no SMuRFs had active cancer and chronic systemic inflammatory diseases (CSIDs), including rheumatoid arthritis and systemic lupus erythematosus, as potential underlying risk factors for MI. 9 Given that the presence of active cancer and CSIDs is independently associated with a worse prognosis in patients with MI in previous reports, [10][11][12][13][14] whether SMuRF-less patients without active cancer and CSIDs have an increased risk of cardiovascular and bleeding events after acute MI remains uncertain.In the present study, we evaluated the clinical characteristics and outcomes of acute MI patients with active cancer, CSIDs, and no SMuRFs.

METHODS
STUDY DESIGN.This was a retrospective, multicenter registry study.Between January 2012 and December 2021, a total of 2,485 patients with acute MI, including both ST-segment elevation and non-STsegment elevation MI, underwent primary percutaneous coronary intervention (PCI) at 4 centers (Chiba University Hospital, Eastern Chiba Medical Center, Chiba Emergency Medical Center, and Chiba Aoba Municipal Hospital) in Japan.7][18][19][20][21][22] This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committees of each center.
Informed consent for this study was ascertained in the form of an opt-out.

DEFINITIONS OF ACTIVE CANCER, CSID, AND
SMuRF.In the present study, patients who were planned to undergo cancer surgery; were receiving anticancer drugs and radiotherapy; and had recurrent, metastatic, and/or inoperable cancer were defined as having active cancer. 104][25][26][27] Patients with CSIDs may have undergone specific medical therapies.Patients with both CSIDs and active cancer (n ¼ 5) were excluded.Thus, 2,480 patients with acute MI undergoing PCI were eventually included in the current analysis.
SMuRFs included hypertension, diabetes, dyslipidemia, and current smoking in this study. 9  and the presence of cardiogenic shock, which is wellknown to be associated with in-hospital mortality in a setting of acute MI, 31 were included in the multivariable analysis.Therapeutic approaches that would be associated with ischemic and bleeding events, including the use of drug-eluting stents, oral anticoagulation, and statins, were also included in the multivariable models.Because medications at discharge were available in the present study, they were not included in the multivariable logistic regression analysis for in-hospital outcomes.Sensitivity analysis was performed for bleeding outcomes after discharge using Fine and Gray subdistribution hazard models considering death as a competing risk.3), and cardiogenic shock, active cancer, and no SMuRFs related to major bleeding events during hospitalization (Table 4).
Among 2,257 patients who survived to discharge, 203 had no follow-up information after discharge.
Thus, follow-up outcomes were assessed in 2,054 patients (Figure 1).Medications at discharge are listed in Table 5.During the median follow-up of 539 days (Q1, Q3: 349, 1,313 days) after discharge, 220 of 2,054 (10.7%) patients developed MACE.The incidence of MACE after discharge was highest in the active cancer group, followed by the CSIDs, no SMuRFs, and SMuRFs groups (Table 6).The Kaplan-Meier analysis demonstrated that patients with active cancer had an increased risk of MACE after discharge than other groups, mainly driven by a higher risk of all-cause death (Central Illustration, Table 6).The risk of recurrent MI did not differ significantly among the 4 groups, while the incidence of ischemic stroke was highest in the CSIDs group, followed by the active cancer, no SMuRFs, and SMuRFs groups (Table 6).
The risk of major bleeding events after discharge was higher in the active cancer group than in other groups (Central Illustration, Table 6).The Cox proportional hazards analysis showed that older age, drug-eluting stents, active cancer, and CSIDs were significantly associated with an increased risk of MACE (Table 7), and that older age, female gender, and active cancer were related to a higher bleeding risk after discharge (Table 8).Competing risk analysis showed similar results in bleeding events after discharge (Supplemental Table S3).

DISCUSSION
In the present multicenter registry, >10% of patients with acute MI were grouped as active cancer, CSIDs, and no SMuRFs in total.In-hospital ischemic events occurred more frequently in patients with no SMuRFs than in other groups, whereas a bleeding risk was  1 and 2. In-hospital clinical outcomes were assessed in the active cancer, chronic systemic inflammatory diseases (CSIDs), no standard modifiable cardiovascular risk factors (SMuRFs), and SMuRFs groups.Outcomes after discharge were also evaluated in patients who survived to discharge and had follow-up information.AMI ¼ acute myocardial infarction; PCI ¼ percutaneous coronary intervention.6][7][8] Among patients with no SMuRFs but developing acute MI, active cancer and CSIDs were potential leading causes of MI, 9 presumably caused by proinflammatory conditions.Given the poor prognosis of patients with cancer and CSIDs after MI, [10][11][12][13][14] such patient groups may have different risk profiles from those with "truly" no SMuRFs.In previous studies, the prevalence of active cancer in patients with acute MI was reported to be 2% to 10%. 10,11,32,33In addition, CSIDs may account for approximately 5% of patients with acute MI.Abbreviations as in Tables 1 and 2.
during the index hospitalization for acute MI and had no follow-up information.Multivariable analysis was performed using logistic regression and the Cox proportional hazard model to estimate unadjusted and adjusted HRs with corresponding 95% CIs of MACE and major bleeding events during the index hospitalization and after discharge.In addition to age and sex, the study groups (the main interest of this study)

J
A C C : A S I A , V O L . 4 , N O .7 , 2 0 2 4

TABLE 2
Values are n (%).MACE ¼ major adverse cardiovascular event(s); other abbreviations as in Table1.J A C C : A S I A , V O L . 4 , N O .7 , 2 0 2 4A P value <0.05 was considered statistically significant.RESULTSOf the 2,480 patients, 104 (4.2%), 94 (3.8%), and 120 (4.8%) were grouped as active cancer, CSIDs, and no SMuRFs.Details of active cancer and CSIDs are listed in Supplemental TablesS1 and S2.Colon cancer was the most common malignancy, followed by blood, lung, and liver cancers (Supplemental TableS1), while rheumatoid arthritis was the leading etiology of CSIDs (Supplemental TableS2).Overall, 142 of 2,480 (5.7%) patients had no SMuRFs, among whom 22 (15.5%) had either active cancer or CSIDs.In the active cancer and CSIDs groups, 14 of 104 (13.5%) and 8 of 94 (8.5%) patients had no SMuRFs, respectively.Baseline patient characteristics are shown in Table1.The mean age was highest in the active cancer group, followed by the no SMuRFs, SMuRFs, and CSIDs groups, and the proportion of women was highest in the CSIDs group (Table1).Cardiogenic shock and cardiac arrest were most frequently observed in the no SMuRFs group (Table1).

TABLE 3
Logistic Regression Analysis for In-Hospital MACE

TABLE 4
Logistic Regression Analysis for In-Hospital Major Bleeding Events Abbreviations as in Table1.highest in the active cancer group.After discharge, a long-term MACE risk was higher in the active cancer and CSIDs groups, and the risk of bleeding was highest in the active cancer group.In any scenario, patients with at least one SMuRFs who did not have active cancer and CSIDs had the lowest risk of ischemic and bleeding events during hospitalization and after discharge, suggesting that the 3 patient groups should be taken into account when managing and treating patients with acute MI because of their vulnerability.ACTIVE CANCER, CSIDs, AND NO SMuRFs IN ACUTE MI.A recent large-scale global study confirmed that SMuRFs are major underlying etiologies of theFIGURE 1 Study Flow

TABLE 6
less likely to be prescribed in the active cancer

TABLE 7
Cox Proportional Hazards Analysis for MACE After Discharge

TABLE 8
Cox Proportional Hazards Analysis for Major Bleeding Events After Discharge Abbreviations as in Tables1 and 2.